REGULATION OF FC GAMMA RECEPTOR SIGNALING BY CD81

CD81 对 FC GAMMA 受体信号传导的调节

• 批准号: 6171339
• 负责人: TONY J FLEMING
• 金额: $ 10.77万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2000-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171339
• 关键词: Arthus phenomenon; CD antigens; anaphylaxis; antibody receptor; biological signal transduction; cytokine; immune complex; immunoglobulin E; laboratory mouse; phagocytosis; protein biosynthesis; receptor coupling

Immune complex-mediated activation of Fc gamma receptors (FcgammaR) on inflammatory cells plays a critical role in the pathogenesis of autoimmune diseases. Fc receptors for IgG (FcgammaRI, FcgammaRIII), IgE (FcepsilonRI) and IgA (FcalphaRI) exhibit a high degree of conservation in signaling including utilization of the same signaling subunits (FcRgamma chains), activation of the same non-receptor tyrosine kinases (NRTK) (syk), and phosphorylation of common downstream substrates (PLCgamma1,cbl, shc). CD81 has been identified as a membrane antigen recognized by antibodies which inhibit FcepsilonRI- and FcgammaRIII- mediated degranulation in mast cells. Since inflammatory cells express both CD81 and FCgammaRs, but not FcepsilonRI, it is reasonable to assume that CD81 could also inhibit FcgammaR- signaling in these cells. The overall objectives of this project are to determine the extent of CD81 inhibition of Fc receptor signaling and the mechanism by which CD81 inhibits FcepsilonRI and FcgammaRIII signaling. Three lines of investigation will be employed to meet these objectives. First, CD81- mediated effects on FcgammaR signaling events such as phagocytosis, cytokine synthesis and degranulation will be examined in normal inflammatory cells and lines. Second, since phosphatases regulate Fc and other antigen receptor signaling, the role of tyrosine phosphatases as effectors of CD81 signaling will be assessed. In addition, CD81- mediated effects on late events of FcR-signaling (ras/MAP kinase, focal adhesion kinase activation) as well as CD81-mediated effects on cell matrix adhesion receptors such as VLA4, will comprise a major part of this line of investigation. Third, further experiments will examine the effect of pretreatment of mice with CD81 antibodies in vivo prior to initiation of IgE- and immune complex-mediated Arthus and anaphylactic reactions. The proposed studies address the extent of CD81 inhibition in FcepsilonRI- and FcgammaR function, its mechanism of action and the potential role of CD81 as an inhibitor of immune complex-mediated activation in vivo, clarification of the role of CD81 in FcgammaR signaling will provide pertinent information as to how FcgammaR activation events are regulated in normal and disease conditions.

免疫复合物介导的 Fc γ 受体 (FcgammaR) 激活 炎症细胞在炎症的发病机制中发挥着重要作用 自身免疫性疾病。 IgG 的 Fc 受体（FcgammaRI、FcgammaRIII）、IgE (FcepsilonRI) 和 IgA (FcalphaRI) 表现出高度保守性 在信令中包括使用相同的信令子单元 （FcRgamma 链），激活相同的非受体酪氨酸激酶 (NRTK) (syk)，以及常见下游底物的磷酸化 （PLCgamma1、cbl、shc）。 CD81已被鉴定为膜抗原 被抑制 FcepsilonRI- 和 FcgammaRIII- 的抗体识别 介导肥大细胞脱颗粒。 由于炎症细胞表达 CD81 和 FCgammaRs，但不是 FcepsilonRI，这是合理的 假设 CD81 也可以抑制这些细胞中的 FcgammaR 信号传导。 该项目的总体目标是确定 CD81 抑制 Fc 受体信号传导及其机制 抑制 FcepsilonRI 和 FcgammaRIII 信号传导。 三行 将进行调查来实现这些目标。 首先，CD81- 对 FcgammaR 信号转导事件（如吞噬作用）的介导作用， 细胞因子合成和脱颗粒将在正常情况下进行检查 炎症细胞和细胞系。 其次，由于磷酸酶调节 Fc 和其他抗原受体信号传导，酪氨酸磷酸酶的作用 作为 CD81 信号传导的效应器将被评估。 此外，CD81- 对 FcR 信号传导（ras/MAP 激酶、局灶性 粘附激酶激活）以及 CD81 介导的细胞效应 基质粘附受体，例如 VLA4，将构成 这条线的调查。 第三，进一步的实验将检验 小鼠体内CD81抗体预处理的效果 IgE 和免疫复合物介导的 Arthus 和过敏反应的启动 反应。 拟议的研究涉及 CD81 抑制的程度 FcepsilonRI-和FcgammaR功能、其作用机制和 CD81作为免疫复合物介导的抑制剂的潜在作用 体内激活，阐明 CD81 在 FcgammaR 中的作用 信号传导将提供有关 FcgammaR 如何 激活事件在正常和疾病条件下受到调节。